Androgen Action through Estrogen Receptor in a Human Breast Cancer Cell Line*

Abstract

Androgens stimulate the growth of the human breast cancer cell line MCF-7. Very high doses are required, however, and therefore, whether they might exert this effect through some mechanism other than the androgen receptor was studied. Evidence is presented that it is actually the estrogen receptor, activated by weak but specific binding of androgens, which mediates this effect. Physiological 5.alpha.-dihydrotestosterone (DHT) at 10-8 M translocates androgen receptor to cell nuclei without affecting other steroid receptors or stimulating cell growth. High DHT (10-6 M) translocates estrogen as well as androgen receptor and stimulates cell growth. Receptors for progestins and glucocorticoids are not affected. Testosterone, 3.beta.-androstanediol, and the antiandrogen, R2956 [17.beta.-hydroxy-2,2,17-trimethylestra-4,9,11-triene-3-one], at 10-6 M also translocate the estrogen receptor, while progesterone, hydrocortisone and the inactive isomer, 5.beta.-DHT, have little or no effect. 5.alpha.-DHT at 10-6 M competes with estradiol for binding to cytosol estrogen receptor, while 10-8 M DHT does not. Estrogen receptor translocated to the nucleus by 10-6 M DHT reaches a peak within 1 h of DHT addition and is then depleted within 3 h to a much lower steady-state level which is then maintained; these actions parallel those of 10-8 M estradiol. Two responses considered specifically estrogenic follow treatment with 10-6 M DHT; neither occurs with physiological 10-8 M DHT. The 1st is stimulation of progesterone receptor synthesis. The 2nd is rescue of cell growth from inhibition by the antiestrogen nafoxidine. The latter action is not prevented by the antiandrogen, R2956, or cyproterone acetate, as would be expected for an androgen receptor action.